DESCRIPTION (provided by applicant: The attention of investigators interested in pain and analgesia has been increasingly directed beyond acute pain mechanisms towards processes that give rise to persistent pain states. There is now clear functional evidence that brainstem modulatory systems contribute to persistent pain associated with nerve injury and inflammation. The best characterized modulatory system has important links in the midbrain periaqueductal gray and rostral ventromedial medulla (RVM), and is recruited to enhance or inhibit nociception under different conditions. The present proposal focuses on the RVM. Over the last ten years, my laboratory has demonstrated that pain-inhibiting and pain- facilitating influences from the RVM are mediated by two classes of neurons, "ON-cells," which exert a net facilitating influence on nociception, and "OFF-cells," which have a net inhibitory action. The overarching goal of this proposal is to understand how activity- dependent changes in the properties and relationships of these neurons contribute to abnormal pain following nerve injury, and during chronic inflammation. Using a combination of single-cell recording and behavioral pharmacology, the proposed experiments will test whether changes in the mechanical thresholds of ON- and OFF-cells in nerve-injured animals are important for behavioral hypersensitivity, contrast changes in RVM neurons during chronic inflammation with those seen following nerve injury, and identify drivers of ON-cell activation in both models. A better understanding of molecular, cellular, and circuit-level mechanisms underlying chronic pain is essential if we are to develop better treatments for patients. There is now increasing evidence that pathological pain states are at least in part driven by changes in the brain itself. Descending modulatory pathways are known to mediate top-down regulation of nociceptive processing, transmitting cortical and limbic influences to the dorsal horn. These pathways are also intimately intertwined with ascending transmission through positive and negative feedback loops. Models of persistent pain that fail to include descending modulatory pathways are thus necessarily incomplete. By examining how the properties of known nociceptive modulatory neurons are transformed during the transition from acute to chronic pain, the present studies fill an important gap in our knowledge. PUBLIC HEALTH RELEVANCE: We now understand that the brain actively controls our sensitivity to painful inputs. An imbalance in the brain's modulatory systems so that pain transmission is favored can therefore be important in chronic pain states. The work proposed in this application will study the properties of pain-modulating neurons in the brainstem to determine how they are altered to support chronic pain.